Project Summary Cognitive decline with aging, including Alzheimer's Disease and Related Dementias (ADRD), is a public health imperative that impacts quality of life and disability. Survivors of acute surgical or medical illness contribute greatly to the crisis of cognitive decline. Hospitalization confers a 1.5-2-fold increase in the odds of new onset dementia. Furthermore, over a third of critically ill patients have new ADRD by 1 year. Major risk factors for ADRD after acute illness include pre-illness frailty and cognitive deficits and delirium in the hospital. Endothelial and blood brain barrier (BBB) dysfunction, cerebral atrophy, and white matter connectivity changes have all been linked to delirium and ADRD. Surgery is common in older adults but it (and its resulting hospitalization) is associated with significant cognitive decline. Individual interventions to reduce this decline have exhibited limited success. Prehabilitation is the process of enhancing capacity and reserve before an acute stressor to improve tolerance of the upcoming insult. Older major surgical patients provide an ideal population for prehabilitation. These patients have lead time prior to surgery, are frequently frail, have prolonged post-surgery ICU and hospital courses, and are at high risk for new ADRD. Prehabilitation studies to date have primarily focused on physical training to improve physical outcomes. Combined physical and computer-based cognitive training programs have been associated with significant improvements in global cognitive function, and computerized brain training exercises have demonstrated enhancement in memory, processing speed, and multitasking. This training, however, has not been examined in surgical or hospitalized patients. We have demonstrated that cognitive training and physical exercises are feasible prior to major surgery and in the hospital, that a combined cognitive and physical rehabilitation program after discharge can reduce ADRD, and that a computerized cognitive rehabilitation program can improve multiple cognitive domains in ICU survivors. Further, exercise enhances endothelial and BBB function, reduces cerebral atrophy, and increases functional connectivity, providing potential mechanistic basis for these improvements. Thus, a comprehensive mind and body training program prior to (prehabilitation), during, and after (rehabilitation) hospitalization may be most effective in reducing ADRD and disability after major surgery but has yet to be evaluated. The main hypothesis of the COgnitive and Physical Exercise to improve Outcomes after Surgery (COPE-iOS) study is that a program of cognitive and physical training throughout the perioperative period will improve long-term cognitive and disability outcomes in older surgical patients at high risk for decline. We will randomize 250 patients ?60 years old undergoing elective major non-cardiac surgery with expected hospitalization >3 days to a comprehensive training program or to active control prior to surgery, during the surgical hospitalization, and after discharge. We will assess global cognition (Aim 1), disability (Aim 2), and plasma biomarkers and neuroimaging (Aim 3) at baseline and up to 12 months after discharge.